OP0013 LOSS OF SYNOVIAL TISSUE MACROPHAGE HOMEOSTASIS PRECEDES RHEUMATOID ARTHRITIS CLINICAL ONSET
Authors: M. Hanlon, M. Canavan, N. Neto, Q. Song, P. Gallagher, R. Mullan, C. Hurson, B. Moran, M. Monaghan, S. Nagpal, D. Veale, U. Fearon
Journal: Annals of the Rheumatic Diseases (2022)

Background Synovial tissue macrophages significantly contribute to Rheumatoid Arthritis, yet the precise nature/function of macrophage subsets within the inflamed joint remains unexplored. Objectives To fully explore the spectrum of distinct macrophage activation states residing within the synovium of RA, at risk and healthy individuals. Methods Single-cell synovial tissue suspensions from RA (n=44), IAR (n=5), HC (n=11), PsA (n=11) and OA (n=4) were obtained, and synovial macrophage subsets examined by advanced multiparameter flow cytometric analysis, bulk RNA-sequencing, metabolic and functional assays. Results Multidimensional analysis identifies enrichment of CD206+CD163+ synovial-tissue macrophages co-expressing CD40 in the RA joint compared to healthy synovial-tissue, with frequency of CD206+CD163+CD40+ macrophages associated with increased disease activity and treatment response. In contrast, CX3CR1-expressing macrophages which form a protective barrier in healthy synovium are significantly depleted in RA. Importantly this signature of enriched CD40 expression coupled with depleted CX3CR1 expression is an early phenomenon, occurring prior to clinical manifestation of disease in individuals ‘at-risk’ of RA (IAR). RNAseq and metabolic profiling of sorted RA synovial-macrophages identified that this population is transcriptionally distinct, displaying unique inflammatory, phagocytic and tissue-resident gene signatures, paralleled by a bioenergetically stable profile as indicated by NAD(P)H emission. Functionally CD206+CD163+ RA macrophages are potent producers of pro-inflammatory mediators (reversed by CD40-signalling inhibition) and induce an invasive phenotype in healthy synovial-fibroblasts. These findings identify a distinct pathogenic population of synovial-tissue macrophage involved in shaping the immune response in RA. Crucially, this signature is present pre-disease representing a unique opportunity for early diagnosis and therapeutic intervention. Conclusion We have identified a novel population of tissue-resident macrophages in the RA synovium which are transcriptionally/metabolically distinct and capable of contributing to disease pathology. Uncovering the molecular patterns and cues that transform this immunoregulatory macrophage population into a dysfunctional inflammatory activation state may provide opportunities to reinstate joint homeostasis in RA patients. Disclosure of Interests Megan Hanlon: None declared, Mary Canavan: None declared, Nuno Neto: None declared, Qingxuan Song Employee of: Employee of Janssen Pharmaceuticals, Phil Gallagher: None declared, Ronan Mullan: None declared, Conor Hurson: None declared, Barry Moran: None declared, Michael Monaghan: None declared, Sunil Nagpal Employee of: Employee of Janssen Pharmaceuticals, Douglas Veale Consultant of: Janssen, Eli Lilly, Pfizer, Ursula Fearon Consultant of: Janssen, Eli Lilly, Pfizer